Azetidinecarboxamide derivatives for treating CNS disorders

ABSTRACT

A compound of formula (1), wherein: R 1  is aryl; R 2  is H, alkyl or aryl; and R 3  is hydrogen or alkyl; pharmaceutically acceptable addition compounds thereof; and the use of the compounds in therapy, particularly for the treatment and prophylaxis of CNS disorders such as anxiety and epilepsy.

This is a 371 of international application PCT/GB99/00219 withinternational filing date Jan. 22, 1999 published in English.

The present invention relates to chemical compounds useful in thetreatment of disorders of the central nervous system (CNS), such asanxiety and all forms of epilepsy, particularly in humans. The inventionalso relates to the use of such compounds, pharmaceutical preparationscontaining such compounds and to methods of preparing such compounds.

Anxiety disorders affect an estimated 73 million people world-wide. Thebenzodiazepines have provided the dominant therapy for anxiety over thepast three decades and there is no doubt that they are remarkablyeffective anxiolytics. However, chronic administration ofbenzodiazepines produces severe dependence liability, withdrawalsyndromes, and side effects (sedation, amnesia, muscle relaxation). Theonly non-benzodiazepine anxiolytic that has been launched over the pastdecade is the 5-HT receptor ligand buspirone (Buspar®). This drug hashad a remarkable commercial success despite being regarded as a weakanxiolytic (compared with the benzodiazepines) and having a long latencyto onset of therapeutic action (2-4 weeks). In addition, buspirone andall related 5-HT_(1A) partial agonists suffer from a dose-limitingside-effect profile comprising nausea, vertigo and endocrine changes.

The aetiology of anxiety disorders is not fully understood, but it isnow established that benzodiazepines act by potentiating GABAergicneurotransmission although there is strong evidence that otherneurotransmitter systems are modulated indirectly—in particular, theserotonergic and noradrenergic systems. Many pharmaceutical companieshave invested considerable resource into the development of serotonergicanxiolytics. However, it is now apparent that ligands selective for 5-HTreceptor subtypes, despite displaying anxiolytic-like activity in arestricted range of anxiety models, have, at best, very weak and/ornon-dose-related anxiolytic effects in the clinic. The 5-HT₃ receptorantagonists are now discredited as psychotropics: they have a restrictedrange of activity in functional and anxiety models; they show noconvincing anxiolytic effects in the clinic; and they are now acceptedonly as useful anti-emetics. The 5-HT_(2A) antagonists similarly areregarded as ineffective in terms of psychotropic activity. The clinicalutility of 5-HT_(1A) receptor agonists and partial agonists is severelylimited by their intrinsically weak action and by the dose-limitingside-effects (vertigo, endocrine changes, nausea) which become moreintense as the agonist efficacy of these molecules is increased. Theselective CCK_(B) receptor antagonists have displayed an unimpressivepreclinical profile similar to that of selective 5-HT ligands such asthe 5-HT₃ antagonists.

Serotonergic anxiolytics include the selective serotonin reuptakeinhibitors (SSRIs) which, in addition to displaying antidepressantproperties, are also effective in anxiety disorders such as panicdisorder and obsessive-compulsive disorder. However, as with theirantidepressant action, the major drawback with these compounds is thelong delay (6-8 weeks) in the onset of clinical improvement followingchronic administration.

A strategy in recent years towards improving the clinical profile ofclassical benzodiazepines is that of developing benzodiazepine receptorpartial agonists, according to the rationale that they would have a moreselective anxiolytic action and be less liable to induce dependence.However, this approach appears to have failed owing to the very weakanxiolytic actions of these compounds and their poor side-effectprofiles (there is either a low or non-existent ratio between anxiolyticand sedative doses).

U.S. Pat. No. 4,956,359 and EP-A-0194112 disclose 3-aryloxy and3-arylthio azetidinecarboxamides and their anti-convulsant andanti-epileptic activity. These compounds, like the benzodiazepines, havelow water solubility which leads to difficulties in formulation. Thepresence of an oxygen or sulphur atom, present as a linking atom betweenthe aryl group and the azetidine ring, is a key feature of thesecompounds since such atoms can affect molecular conformation as well asincreasing electron density in the aryl rings.

There remains therefore a need for novel anxiolytic and anti-epilepticagents which do not suffer the above-mentioned drawbacks.

It has now been surprisingly found that inserting a methylene-containinggroup between the aryl group and the oxygen atom, and thereby increasingconformational freedom and decreasing election density in the aryl ring,is not detrimental to pharmacological effect. Further, insertion of themethylene-containing group gives a surprising improvement in the bindingaffinity to the GABA_(A) receptor.

According to the present invention there is provided a chemical compoundof formula (1)

wherein:

R¹ is aryl;

R² is H, alkyl or aryl; and

R³ is hydrogen or alkyl;

and pharmaceutically acceptable addition compounds thereof.

Reference in the present specification to an “alkyl” group means abranched or unbranched, cyclic or acyclic, saturated or unsaturated(e.g. alkenyl or alkynyl) hydrocarbyl radical. Where cyclic or acyclicthe alkyl group is preferably C₁ to C₁₂, more preferably C₁ to C₈ (suchas methyl, ethyl, propyl, isopropyl butyl, isobutyl, tert-butyl, amyl,isoamyl, hexyl, heptyl, octyl).

Reference in the present specification to an “aryl” group means a monoor bicyclic aromatic group, such as phenyl or naphthyl.

The alkyl and aryl groups may be substituted or unsubstituted. Wheresubstituted, there will generally be 1 to 3 substituents present,preferably 1 or 2 substituents. Substituents may include:

carbon containing groups such as

alkyl

aryl, arylalkyl (e.g. substituted and unsubstituted phenyl, substitutedand unsubstituted benzyl);

halogen atoms and halogen containing groups such as haloalkyl (e.g.trifluoromethyl);

oxygen containing groups such as

alcohols (e.g. hydroxy, hydroxyalkyl, (aryl)(hydroxy)alkyl),

ethers (e.g. alkoxy, alkoxyalkyl, aryloxyalkyl),

aldehydes (e.g. carboxaldehyde),

ketones (e.g. alkylcarbonyl, alkylcarbonylalkyl, arylcarbonyl,arylalkylcarbonyl, arylcarbonylalkyl),

acids (e.g. carboxy, carboxyalkyl),

acid derivatives such as esters

(e.g. alkoxycarbonyl, alkoxycarbonylalkyl, alkycarbonylyoxy,alkycarbonylyoxyalkyl) and amides

(e.g. aminocarbonyl, mono- or dialkylaminocarbonyl, aminocarbonylalkyl,mono- or dialkylaminocarbonylalkyl, arylaminocarbonyl);

nitrogen containing groups such as

amines (e.g. amino, mono- or dialkylamino, aminoalkyl, mono- ordialkylaminoalkyl),

azides,

nitriles (e.g. cyano, cyanoalkyl),

nitro;

sulphur containing groups such as

thiols, thioethers, sulphoxides and sulphones

(e.g. alkylthio, alkylsulfinyl, alkylsufonyl, alkylthioalkyl,alkylsulfinylalkyl,

alkylsulfonylalkyl, arylthio, arylsulfinyl, arylsulfonyl, arylthioalkyl,arylsulfinylalkyl, arylsulfonylalkyl);

and heterocyclic groups containing one or more, preferably one,heteroatom,

(e.g. thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl,isothiazolyl, oxazolyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl,imidazolinyl, pyrazolidinyl, tetrahydrofuranyl, pyranyl, pyronyl,pyridyl, pyrazinyl, pyridazinyl, piperidyl, piperazinyl, morpholinyl,thionaphthyl, benzofuranyl, isobenzofuryl, indolyl, oxyindolyl,isoindolyl, indazolyl, indolinyl, 7-azaindolyl, isoindazolyl,benzopyranyl, coumarinyl, isocoumarinyl, quinolyl, isoquinolyl,naphthridinyl, cinnolinyl, quinazolinyl, pyridopyridyl, benzoxazinyl,quinoxadinyl, chromenyl, chromanyl, isochromanyl and carbolinyl).

Preferred substituents include alkyl, aryl, nitrile, halo, or ahalogen-containing group such as trifluoromethyl.

As used herein, the term “alkoxy” means alkyl-O— and “alkoyl” meansalkyl-CO—.

As used herein, the term “halogen” means a fluorine, chlorine, bromineor iodine radical, preferably a fluorine or chlorine radical.

The compounds of formula (1) may exist in a number of diastereomericand/or enantiomeric forms. Reference in the present specification to “acompound of formula (1)” is a reference to all stereoisomeric forms ofthe compound and includes a reference to the unseparated stereoisomersin a mixture, racemic or non-racemic, and to each stereoisomer in itspure form.

In the compounds of formula (1), preferably R¹ is a substituted orunsubstituted aryl group selected from phenyl and naphthyl, morepreferably R¹ is a substituted phenyl or naphthyl, more preferably R¹ isa phenyl or naphthyl having 1 to 3 substituents and most preferably R¹is a phenyl or naphthyl having 1 or 2 substituents. In a preferredembodiment of the invention, R¹ is a mono- or di-substituted phenylgroup, preferably a mono-substituted phenyl group.

Where R¹ is a naphthyl group, R¹ is preferably a 2-naphthyl group.

Where R¹ is a phenyl having 1 substituent, the phenyl group ispreferably para- or meta-substituted. Where R¹ is a phenyl having 2substituents, the phenyl group is preferably 2,4-disubstituted,2,5-disubstituted, 3,4-disubstituted or 3,5 disubstituted, and morepreferably 3,4-disubstituted.

The preferred substituent groups are selected from halo (preferablyfluoro and chloro), trifluoromethyl, tertiary-butyl, phenyl and CN.

Where R¹ is disubstituted, it is preferred that R¹ is substituted by twohalo groups, the same or different, preferably the same, or by twotrifluoromethyl groups.

The most preferred R¹ groups are selected from 3-chlorophenyl,3-fluorophenyl, 4-chlorophenyl, 4-fluorophenyl, 3-trifluoromethylphenyl,4-trifluoromethylphenyl, 3,4-dichlorophenyl and 3,4-difluorophenyl.

In the compound of formula (1), preferably R² is H, C₁₋₄ alkyl ormono-substituted phenyl. Where R² is C₁₋₄ alkyl, it is preferred that R²is acyclic hydrocarbyl, preferably methyl or ethyl. Where R² ismono-substituted phenyl, it is preferred that R² is a halo-substitutedphenyl, preferably substituted in the para-position.

In one embodiment of the present invention, R³ is alkyl, preferably C₁₋₄alkyl, and more preferably alkenyl, alkynyl, hydroxyalkyl, alkoxyalkylor unsubstituted saturated cyclic or acyclic hydrocarbyl.

In a further embodiment of the present invention, R³ is selected from Hand C₁₋₄ alkyl, preferably from H, alkenyl, alkynyl, hydroxyalkyl,alkoxyalkyl and unsubstituted saturated cyclic and acyclic hydrocarbyl,and more preferably from H, propyl, 2-propenyl, 2-propynyl and2-hydroxypropyl.

Particularly preferred compounds are as follows:

R¹ R² R³ 4-Cl—C₆H₄ H 2-propenyl 3,4-Cl₂—C₆H₃ H 2-propenyl 3,4-F₂—C₆H₃ H2-propenyl 3-CF₃—C₆H₄ H 2-propenyl 4-CF₃—C₆H₄ H 2-propenyl 4-F—C₆H₄ H2-propenyl 4-F—C₆H₄ H 2-propynyl 4-Cl—C₆H₄ H 2-propynyl 4-Cl—C₆H₄4-Cl—C₆H₄ 2-propenyl 4-Cl—C₆H₄ 4-Cl—C₆H₄ 2-hydroxypropyl 3-CF₃—C₆H₄ H H3-CF₃—C₆H₄ methyl H

Of these, the preferred compounds are3-(3,4-Dichlorobenzyloxy)-N-(2-propenyl)azetidine-1-carboxamide,3-(3-(Trifluoromethyl)benzyloxy)-N-(2-propenyl)azetidine-1-carboxamide,3-(4-(Trifluoromethyl)benzyloxy)-N-(2-propenyl)azetidine-1-carboxamide,3-(4-Fluorobenzyloxy)-N-(2-propenyl)azetidine-1-carboxamide,3-(Bis(4-chlorophenyl)methoxy)-N-(2-propenyl)azetidine-1-carboxamide,(R)-3-(Bis(4-chlorophenyl)methoxy)-N-(2-hydroxypropyl)azetidine-1-carboxamide,3-(1-(3-Trifluoromethylphenyl)ethyloxy)-azetidine-1-carboxamide, and3-(3-(Trifluoromethyl)benzyloxy)-azetidine-1-carboxamide.

According to a further aspect of the present invention there is provideda compound according to the present invention for use in therapy.

The compounds of the present invention may be used in the treatment(including prophylaxis) of CNS disorders. In particular, the compoundsof the present invention may be used in the treatment (includingprophylaxis) of anxiety, epilepsy, insomnia, including travel insomniaand insomnia associated with terminal illness, alcohol withdrawalsyndrome, chronic and acute pain, neurodegenerative diseases (forexample, senile dementia) and symptoms related to withdrawal fromsubstance abuse. The compounds may also be used in the relief ofspasticity. The compounds of the present invention may also be used inmuscle relaxation prior to surgery or surgical manipulation or aspre-medication prior to surgery. In a preferred embodiment of thepresent invention, the compounds are used in the treatment (includingprophylaxis) of anxiety or epilepsy.

Anxiety includes generalised anxiety disorder (GAD), panic disorder,panic disorder plus agoraphobia, simple (specific) phobias (e.g.arachnophobia, performance anxiety such as public speaking), socialphobias, post-traumatic stress disorder, anxiety associated withdepression, and obsessive compulsive disorder (OCD).

Epilepsy is a chronic disorder characterised by recurrent seizures. Twoforms of epilepsy exist—partial and generalised epilepsy—and each typeis subdivided into idiopathic (cause unknown) or symptomatic (causeknown). There are two fundamental types of seizures: partial seizureswhich includes simple partial seizures, complex partial seizures, andpartial seizures secondarily generalised; and generalised seizures whichincludes generalised tonic-clonic seizures (grand mal), absence seizures(petit mal), myoclonic seizures, atonic seizures, clonic seizures, andtonic seizures.

According to a further aspect of the present invention there is provideduse of a compound of the present invention in the manufacture of amedicament for the treatment (including prophylaxis) of CNS disorders,preferably anxiety, epilepsy, insomnia, including travel insomnia andinsomnia associated with terminal illness, alcohol withdrawal syndrome,chronic and acute pain, neurodegenerative diseases, symptoms relating towithdrawal from substance abuse or spasticity, and more preferablyanxiety or epilepsy.

According to a further aspect of the present invention there is provideduse of a compound of the present invention in the manufacture of amedicament for muscle relaxation prior to surgery or surgicalmanipulation or as pre-medication prior to surgery.

The invention further provides a method of treatment (includingprophylaxis) of CNS disorders, preferably anxiety, epilepsy, insomnia,including travel insomnia and insomnia associated with terminal illness,alcohol withdrawal syndrome, chronic and acute pain, neurodegenerativediseases, symptoms relating to withdrawal from substance abuse andspasticity, and more preferably anxiety or epilepsy, comprisingadministering to a patient in need of such treatment an effective doseof a compound according to the present invention.

The invention further provides a method of muscle relaxation prior tosurgery or surgical manipulation or a method of pre-medication prior tosurgery, comprising administering to a patient in need thereof aneffective dose of a compound according to the present invention.

According to a further aspect of the present invention there is provideda method of preparing a compound of the present invention.

Compounds of the present invention may be prepared according to thereaction scheme (where P is a nitrogen protecting group). R¹, R², and R³are as previously defined. The ether (IV) may be formed by reaction ofthe azetidinol (II) either with an arylalkanol (III, X═OH) anddiethylazo dicarboxylate and triphenyl phosphine or with an arylalkylchloride, bromide, iodide, mesylate or tosylate (III, X═Cl,Br,I,mesylate, tosylate) and a strong base such as sodium hydride. Formationof the azetidine (V) may be achieved by reaction of (IV) with a suitablenitrogen deprotection agent. For example, if P is a diphenylmethylgroup, then deprotection may be carried out by treatment with1-chloroethyl chloroformate followed by methanol. The urea (I) is formedby reaction of azetidine (V) with an N-alkylisocyanate or anN-alkylcarbamoyl chloride and a base such as triethylamine or potassiumcarbonate. Alternatively, the urea may be prepared directly from theazetidine (IV) without isolation of an intermediate such as thesecondary amine (V). For example, when P is a diphenylmethyl group,azetidine (IV) may be treated with phosgene followed by amine R³NH₂ togive urea (I) directly.

The invention further provides a pharmaceutical composition comprising acompound according to the present invention in combination with apharmaceutically acceptable carrier or excipient and a method of makingsuch a composition comprising combining a compound according to thepresent invention with a pharmaceutically acceptable carrier orexcipient.

Compounds of the present invention may be administered in a formsuitable for oral use, for example a tablet, capsule, aqueous or oilysolution, suspension or emulsion; for topical use including transmucosaland transdermal use, for example a cream, ointment, gel, aqueous or oilsolution or suspension, salve, patch or plaster; for nasal use, for aexample a snuff, nasal spray or nasal drops; for vaginal or rectal use,for example a suppository; for administration by inhalation, for examplea finely divided powder or a liquid aerosol; for sub-lingual or buccaluse, for example a tablet or capsule; or for parenteral use (includingintravenous, subcutaneous, intramuscular, intravascular or infusion),for example a sterile aqueous or oil solution or suspension. In generalthe above compositions may be prepared in a conventional manner usingconventional excipients, using standard techniques well known to thoseskilled in the art of pharmacy. Preferably, the compound is administeredorally.

For oral administration, the compounds of the invention will generallybe provided in the form of tablets or capsules or as an aqueous solutionor suspension.

Tablets for oral use may include the active ingredient mixed withpharmaceutically acceptable excipients such as inert diluents,disintegrating agents, binding agents, lubricating agents, sweeteningagents, flavouring agents, colouring agents and preservatives. Suitableinert diluents include sodium and calcium carbonate, sodium and calciumphosphate, and lactose, while corn starch and alginic acid are suitabledisintegrating agents. Binding agents may include starch and gelatin,while the lubricating agent, if present, will generally be magnesiumstearate, stearic acid or talc. If desired, the tablets may be coatedwith a material such as glyceryl monostearate or glyceryl distearate, todelay absorption in the gastrointestinal tract.

Capsules for oral use include hard gelatin capsules in which the activeingredient is mixed with a solid diluent, and soft gelatin capsuleswherein the active ingredient is mixed with water or an oil such aspeanut oil, liquid paraffin or olive oil.

For intramuscular, intraperitoneal, subcutaneous and intravenous use,the compounds of the invention will generally be provided in sterileaqueous solutions or suspensions, buffered to an appropriate pH andisotonicity. Suitable aqueous vehicles include Ringer's solution andisotonic sodium chloride. Aqueous suspensions according to the inventionmay include suspending agents such as cellulose derivatives, sodiumalginate, polyvinyl-pyrrolidone and gum tragacanth, and a wetting agentsuch as lecithin. Suitable preservatives for aqueous suspensions includeethyl and n-propyl p-hydroxybenzoate.

It will be appreciated that the dosage levels used may vary over quite awide range depending upon the compound used, the severity of thesymptoms exhibited by the patient and the patient's body weight.

The invention will now be described in detail with reference to thefollowing examples. It will be appreciated that the invention isdescribed by way of example only and modification of detail may be madewithout departing from the scope of the invention.

EXPERIMENTAL Measurement of Binding Affinity to the GABA_(A) Receptorwith [³⁵S]-TBPS

The ability of test compounds to bind to the GABA_(A) receptor wasmeasured in membranes prepared from rat fore-brain using the proceduredescribed by Green et al (Green, A. R., Misra, A., Murray, T. K., Snape,M. F. & Cross, A. J. Neurophamacology, 1996, 35, 1243-1250).

Binding assays were performed in plastic microtitre plates. In eachstudy total assay volume contained [³⁵S]-TBPS (1 nM finalconcentration), membrane preparation and displacing drugs whereappropriate. Drug solutions were prepared at a concentration of 10 mM inan appropriate solvent (EtOH, DMSO or H₂O) and then diluted with assaybuffer. Non-specific binding was determined using GABA. The free ligandconcentration was determined by counting aliquots of the [³⁵S]-TBPSsolution. The concentration of test compounds required to displace 50%of the specific binding (IC₅₀) was determined from displacement curves.The test results are shown in Table 1

TABLE 1 Binding Affinities to the GABA_(A) receptor Example number IC₅₀(μM) 2 56 3 87 4 91 6 64 7 32

Antagonism of 3-MPA-Induced Seizures

Several animal seizure models are available for the screening andcharacterisation of anticonvulsant (antiepileptic) drugs. Most modelsemploy a chemical convulsant to induce seizures and the anticonvulsantpotencies of novel compounds are measured in terms of their ability toincrease the dose of convulsant required to induce a seizure response(or to prolong the latency to seizure onset following a bolus dose ofthe convulsant). Most chemical convulsants work by blocking theneurotransmitter function of gamma-aminobutyric acid (GABA), thepredominant inhibitory neurotransmitter in the mammalian brain. This canbe achieved by blocking the postsynaptic action of GABA usingpentylenetetrazol or bicuculline, or via a presynaptic action using aGABA synthesis inhibitor to decrease GABA release into the synapse. Inthis case, the inhibitor of glutamate decarboxylase (GAD),3-mercaptopropionic acid (3-MPA), was used as the convulsant challengeagent. Anticonvulsant effects of test compounds were determined by theirabilities to significantly increase the dose of 3-MPA required toinitiate a seizure response.

Male albino T/O strain mice (obtained from Tuck) weighing 28-40 g wereused in these studies. Animals were assigned randomly to treatmentgroups and vehicle or test drug (at a dose of 30 mg/kg) wereadministered p.o. to groups of 12 animals 60 min before theadministration of a bolus dose of 3-MPA intravenously. Immediatelyfollowing 3-MPA administration, each mouse was placed individually intoa cage for observation. The seizure response of each animal was scoredquantally as present or absent (response or non-response) during the 5min period immediately following 3-MPA administration. A seizureresponse was defined as the onset of the initial clonic phase of theseizure (abrupt loss of righting reflex accompanied by vocalisation).The seizure threshold (in terms of mg/kg i.v. of 3-MPA required to evokea seizure response) was determined in each treatment group by asequential up/down method followed by modified probit analysis of thequantal data. A range of doses of 3-MPA was prepared (12.5-200.0 mg/kgi.v.) increasing by a constant geometric factor (³2), which was found inpilot studies to generate suitable data for analysis by this method.

In these studies, 3-MPA was obtained from Sigma.

Test compounds were prepared as solutions dissolved in 45% w/v aqueous2-hydroxypropyl-β-cyclodextrin. 3-MPA was dissolved in isotonic salineand its pH adjusted to 6 using 1M sodium hydroxide solution. Drugs wereadministered in a dose volume of 10 ml/kg body weight. The test resultsare shown in Table 2.

TABLE 2 Antagonism of 3-MPA-Induced Seizures: Results of TestingCompound SC SV Example 1 35.98 15.7 Example 2 66.7 16.2 Example 3 129.315.6 Example 4 75.7 16.2 Example 5 42.8 15.6

SC=seizure threshold after treatment with test drug

SV=seizure threshold in vehicle treated group

Measurement of Anxiolytic Activity in Mice Using the Elevated Zero-mazeModel

The elevated “zero-maze” is a modification of the elevated plus-mazemodel of anxiety which incorporates both traditional and novelethological measures in the analysis of drug effects (Shepherd, J. K.,Grewal, S. S., Fletcher, A., Bill, D. J. and Dourish, C. T., Behaviouraland pharmacological characterisation of the elevated “zero-maze” as ananimal model of anxiety. Psychopharmacology, 1994, 116, 56-64).

Male Sprague-Dawley rats (Charles River) weighing 300-450 gm are used.Animals are group-housed (5 per cage; cage size: 40×40×20 cm) in atemperature-controlled environment (20±2° C.), under a 12h light-darkcycle (lights on: 08:00 hours). Food and water are made freelyavailable. Four hours prior to testing, animals are transferred to cleancages and moved to the testing room in order to habituate to the testingenvironment.

The maze is comprised of a black Perspex annular platform (105 cmdiameter, 10 cm width) elevated to 65 cm above ground level, dividedequally into four quadrants. Two opposite quadrants are enclosed byclear red Perspex walls (27 cm high) on both the inner and outer edgesof the platform, while the remaining two opposite quadrants aresurrounded only by a Perspex “lip” (1 cm high) which serves as a tactileguide to animals on these open areas. To facilitate the measurement oflocomotor activity, the apparatus is divided into octants by splittingeach quadrant into equal halves using high contrast white lines. Theapparatus is illuminated by dim red lighting arranged in such a manneras to provide similar lux levels in both the open and closed quadrants(40-60 lux). A video camera, connected to a VCR in an adjacentobservation room, is mounted overhead in order to record behaviour onthe maze for subsequent analysis.

Chlordiazepoxide hydrochloride [CDP; Sigma Chemical Co. Ltd. Poole],which has previously been shown to display robust anxiolytic-likeeffects in the zero-maze, serves as positive control. Drugs aretypically dissolved in a 45% solution of 2-hydroxypropyl-β-cyclodextrin,and administered orally by gavage 1 hour prior to zero-maze testing.

Rats are placed on a closed quadrant and a 5 min test period is recordedon video-tape. The maze is cleaned with a 5% methanol/water solution anddried thoroughly between test sessions. Five behavioural parameters arescored: [1] percentage of time spent on the open areas; [2] frequency ofhead dips over the edge of the platform when subjects are located ineither the open or the end of the closed quadrants; [3] frequency ofstretch-attend postures (SAP) from closed to open quadrants, determinedwhen the subject, on a closed quadrant, exhibits an elongated bodyposture stretched forward with at least the snout passing over theopen/close divide; [4] frequency of rearing; and [5] the number of linecrossings. Animals are scored as being in the open area when all fourpaws were in an open quadrant, and in the closed area only when all fourpaws passed over the open/closed divide. All testing is carried outbetween 1100 and 1700 hours.

An increase in the frequency of head dips is considered to be a measureof anxiolytic activity. The compound of example 1 was found to beeffective at a dose of 30 mg/Kg.

CHEMISTRY Preparation of 1-(Diphenylmethyl)-3-azetidinol

This compound was prepared according to the method of Anderson and Lok(J. Org. Chem., 1972, 37, 3953, the disclosure of which is incorporatedherein by reference), m.p. 111-112° C. (lit. m.p. 113° C.).

Preparation of 3-(4-Chlorobenzyloxy)-1-(diphenylmethyl) azetidine (1)

A solution of 1-diphenylmethyl-3-azetidinol (25 mmol) in DMF (100 mL)was added at 0° C. to a suspension of NaH (60% disp.in oil, 30 mmol) inDMF (50 mL). The reaction mixture was stirred at room temperature for 1h, then 4-chlorobenzylchloride (25 mmol) was added dropwise at 0° C. andthe reaction mixture stirred at room temperature for 3 h. The reactionwas quenched with water and extracted with ethyl acetate (3×50 mL), theextracts were washed with water and brine, dried (MgSO₄) andconcentrated in vacuo. The residue was purified by chromatography [SiO₂;hexane-ethyl acetate (9:1)] to yield the product as a yellow oil (7.3 g,80%). The material was used in the next step without furtherpurification.

Example 1 3-(4-Chlorobenzyloxy)-N-(2-propenyl)azetidine-1-carboxamide(2)

Phosgene solution (1.75-M in toluene, 24 mmol) was added at 0° C. to asolution of compound (1) (20 mmol) in CH₂Cl₂ (40 mL). The reactionmixture was stirred at room temperature for 90 min, concentrated invacuo, then redissolved in CH₂Cl₂ (40 mL) and treated with allylamine(42 mmol) at 0° C. The reaction was stirred for 4 h at room temperature,then water (40 mL) was added and the layers were separated. The aqueouslayer was extracted with further CH₂Cl₂ (2×40 mL). The organic layerswere washed with dilute HCl (20 mmol) and brine, dried (MgSO₄) andconcentrated in vacuo. The residue was triturated using diethyl ether togive the product (2) as a crystalline solid (3.5 g, 60%), m.p. 110-111°C. Found: C, 59.84; H, 6.11; N, 9.98. C₁₄H₁₇ClN₂O₂ requires: C, 59.89;H, 9.6.10; N, 9.97%.

Preparation of 3-(3,4-Dichlorobenzyloxy)-1-(diphenylmethyl)azetidine (3)

This material was prepared from 1-diphenylmethyl-3-azetidinol (6.0 g)and alpha,3,4-trichlorotoluene using the procedure described forcompound (1) (yield 92%).

Example 23-(3,4-Dichlorobenzyloxy)-N-(2-propenyl)azetidine-1-carboxamide (4)

This material was prepared from compound (3) (9.2 g) using the proceduredescribed for compound (2) (yield 75%), m.p. 88-89° C. Found: C, 53.43;H, 5.18; N, 8.85, C₁₄H₁₆Cl₂N₂O₂ requires C, 53.35; H, 5.12; N, 8.88%.

Preparation of3-(3-(Trifluoromethyl)benzyloxy)-1-(diphenylmethyl)azetidine (5)

This material was prepared from 1-diphenylmethyl-3-azetidinol (5 g) andalpha′-bromo-alpha,alpha,alpha-trifluoro-m-xylene using the proceduredescribed for compound (1) (yield 91%).

Example 33-(3-(Trifluoromethyl)benzyloxy)-N-(2-propenyl)azetidine-1-carboxamide(6)

This material was prepared from compound (5) (7.5 g) using the proceduredescribed for compound (1) (yield 64%), m.p. 108° C. Found: C, 57.29; H,5.44; N, 8.87, C₁₅H₁₇F₃N₂O₂ requires C, 57.32; H, 5.45; N, 8.91%.

Preparation of3-(4-(Trifluoromethyl)benzyloxy)-1-(diphenylmethyl)azetidine (7)

This material was prepared from 1-diphenylmethyl-3-azetidinol (6.0 g)and α′-bromo-α,α,α-trifluoro-p-xylene using the procedure described forcompound (1) (yield 77%).

Example 43-(4-(Trifluoromethyl)benzyloxy)-N-(2-propenyl)azetidine-1-carboxamide(8)

This material was prepared from compound (7) (7.7 g) using the proceduredescribed for compound (2) (yield 72%), m.p. 120° C. Found: C, 57.27; H,5.45; N, 8.86. C₁₅H₁₇F₃N₂O₂ requires C, 57.32; H, 5.45, N, 8.91%.

Preparation of 3-(4-Fluorobenzyloxy)-1-(diphenylmethyl)azetidine (9)

This material was prepared from 1-diphenylmethyl-3-azetidinol (6.0 g)and 4-fluorobenzyl bromide using the procedure described for compound(1) (yield 83%).

Example 5 3-(4-Fluorobenzyloxy)-N-(2-propenyl)azetidine-1-carboxamide(10)

This material was prepared from compound (9) using the proceduredescribed for compound (2), m.p. 97-99° C. Found: C, 63.57; H, 6.59; N,10.66. C₁₄H₁₇ClN₂O₂ requires C, 63.62; H, 6.48; N, 10.59.

Preparation of 3-(Bis-(4-chlorophenyl)methoxy-1-diphenylmethyl)azetidine(11)

A solution of 4,4′-dichlorobenzhydrol (25 mmol),p-toluenesulfonic acid(18.4 mmol) and 1-(diphenylmethyl)-3-azetidinol (8.4 mmol) in benzene(100 mL) was heated under reflux in a Dean-Stark apparatus for 3 h. Thesolution was cooled, washed with sodium hydrogen carbonate (saturatedaqueous solution, 100 mL), dried (MgSO₄) and concentrated in vacuo. Theresidue was purified by chromatography [SiO₂; hexane-diethyl ether(5:1)] to yield the product (11) as a thick oil that crystallized onstanding (2.4 g, 62%).

Example 63-(Bis(4-chlorophenyl)methoxy)-N-(2-propenyl)azetidine-1-carboxamide(12)

This material was prepared from compound (11) using the proceduredescribed for compound (2) (yield 17%) as a crystalline solid. Found: C,56.38; H, 5.10; N, 6.51. C₂₀H₂₀Cl₂N₂O₂.2H₂O requires: C, 56.21; H, 5.66;N, 6.56%.

Example 7 Preparation of(R)-3-(Bis(4-chlorophenyl)methoxy)-N-(2-hydroxypropyl)azetidine-1-carboxamide(13)

This material was prepared from compound (11) and(R)-(−)-1-amino-2-propanol using the procedure described for compound(2) (yield 57%) as a crystalline solid. Found: C, 58.74; H, 5.42; N,6.84. C₂₀H₂₂Cl₂N₂O₃ requires: C, 58.69; H, 5.42; N, 6.84%.

Example 8 3-(3-Trifluoromethyl)benzyloxy-N-azetidine-1-carboxamide (14)

To a solution of3-(3-trifluoromethyl)benzyloxy-1-(diphenylmethyl)azetidine (5) (5.3mmol) in dichloromethane (15 mL) at 0° C., was added a solution ofphosgene (1.75M in toluene, 6.4 mmol). The reaction mixture was stirredat room temperature for 2 h, concentrated in vacuo, then redissolved inTHF (15 mL) and treated with ammonium hydroxide (5 mL), added in oneportion, at 0° C. The reaction was stirred vigorously for 15 h at roomtemperature, then water (50 mL) and ethyl acetate (40 mL) were added andthe layers were separated. The aqueous layer was extracted with ethylacetate (2×40 mL), dried (MgSO₄) and concentrated in vacuo. The residuewas triturated using ethyl acetate (10 mL) to yield (14) as a solid(0.91 g, 63%), mp. 167° C. (ethyl acetate). Found: C, 52.44; H, 4.72; N,10.23. C₁₄H₁₇ClN₂O₂ requires: C, 52.56; H, 4.78; N, 10.21.

Preparation of3-(1-(3-Trifluoromethylphenyl)ethyloxy)-1-(diphenylmethyl)azetidine (15)

To a solution of α-methyl-3-trifluoromethylbenzyl alcohol (53 mmol),diisopropylethyl amine (105 mmol) in dichloromethane (150 mL) undernitrogen and cooled to 0° C., was added methane sulfonyl chloride (63.1mmol) dropwise over 10 min. The reaction was stirred for 15 h. Water(200 mL) was added and the resulting mixture stirred for 10 min, pouredinto potassium carbonate (10% wt/wt aqueous solution, 200 mL) andextracted with dichloromethane (3×150 mL). Combined organic extractswere washed with brine (50 mL) once and then dried (Na₂SO₄), filteredand concentrated in vacuo. The residue was dissolved in ethyl ether andwashed through a pad of silica, eluting with more ether. The filtratewas concentrated in vacuo. This material was used directly, as shownbelow.

A solution of 1-diphenylmethyl-3-azetidinol (42 mmol) in dimethylformamide (20 mL) was added via pipette, to a suspension of NaH (60%disp.in oil, 50 mmol) in dimethyl formamide (80 mL) at 0° C. Thereaction mixture was stirred at room temperature for 15 min, the crudematerial from above (assumed 53 mmol) was added dropwise as a solutionin dimethyl formamide (30 mL) at 0° C. and the reaction mixture stirredat room temperature for 2 h. The reaction was poured into water (200 mL)and extracted with ethyl acetate (3×50 mL), the extracts were washedwith water (200 mL) and brine (50 mL), dried (MgSO₄) and concentrated invacuo. The residue was purified by chromatography (SiO₂; hexane/ethylacetate 9/1) to yield3-(1-(3-trifluoromethylphenyl)ethyloxy)-1-(diphenylmethyl)azetidine (15)as a yellow oil (11.2 g, yield 65%). The material was used in the nextstep without further purification.

Example 93-(1-(3-Trifluoromethylphenyl)ethyloxy)-azetidine-1-carboxamide (16)

This material was prepared from compound (15) using the proceduredescribed for compound (14) (yield 62%) as a crystalline solid, mp.130.5-131.5° C. (diisopropyl ether). Found: C, 54.24; H, 5.26; N, 9.69.C₁₄H₁₇ClN₂O₂ requires: C, 54.17; H, 5.24.; N, 9.71.

Examples 10 to 43

see Table 3.

The products were prepared using the procedure described for compound(2).

TABLE 3 Exampleno Compound No. Structure Formula MWt mp Cfound HfoundNfound Cexp Hexp Nexp Note 10 17

C15H17N3O2 271.32 95-96 66.69 6.29 15.32 66.40 6.32 15.48 11 18

C20H22N2O2 322.41 160.0 74.52 6.87 8.61 74.51 6.88 8.68 12 19

C18H20N2O2 296.37 141-142 72.96 6.77 9.65 72.95 6.80 9.45 13 20

C14H18Cl2N2O2 317.22 89-90 53.00 5.74 8.73 53.01 5.72 8.83 14 21

C14H17ClN2O2 280.76 67-68 59.94 6.12 9.95 59.89 6.10 9.97 15 22

C14H17FN2O2 264.30 59-60 63.55 6.55 10.59 63.62 6.48 10.59 16 23

C15H19F3N2O2 316.33 128-129 56.92 6.09 8.83 56.96 6.05 8.85 17 24

C15H19F3N2O2 316.33 62-63 56.89 6.21 8.82 56.96 6.05 8.85 18 25

C15H19F3N2O3 332.33 67-68 54.25 5.81 8.42 54.21 5.76 8.43 19 26

C15H19F3N2O3 332.33 67-68 54.21 5.87 8.41 54.21 5.76 8.43 20 27

C15H19F3N2O3 332.33 97-98 54.09 5.76 8.39 54.21 5.76 8.43 21 28

C15H19F3N2O3 332.33 97-98 54.39 5.82 8.44 54.21 5.76 8.43 22 29

C14H18Cl2N2O3 333.22 88-89 50.46 5.34 8.39 50.46 5.44 8.40 23 30

C14H18Cl2N2O3 333.22 88-89 50.49 5.36 8.61 50.46 5.44 8.40 24 31

C14H19ClN2O3 298.77 85-86 56.27 6.40 9.35 56.28 6.41 9.37 25 32

C15H15F3N2O2 312.29 90-91 57.73 4.94 8.91 57.69 4.84 8.97 26 33

C14H18N2O2 246.31 76-77 68.29 7.35 11.37 68.27 7.37 11.37 27 34

C14H19FN2O3 282.32 73-74 59.49 6.87 9.93 59.56 6.78 9.92 28 35

C1H17F3N2O2 314.31 63.0 57.34 5.47 8.92 57.32 5.45 8.91 29 36

C14H16F2N2O2 282.29 75.0 59.59 5.72 9.88 59.57 5.71 9.92 30 37

C14H16Cl2N2O2 315.20 100.0 53.15 4.99 8.86 53.35 5.12 8.88 31 38

C14H16F2N2O2 282.29 79.0 59.55 5.73 9.90 59.57 5.71 9.92 32 39

C16H19F3N2O2 328.34 oil a 33 40

C14H16F2N2O2 282.29 82.5-85   59.72 5.69 9.98 59.57 5.71 9.92 34 41

C14H16F2N2O2 282.29   91-92.5 59.58 5.62 9.94 59.51 5.71 9.92 35 42

C16H16F6N2O2 382.31 80.5-81.5 50.38 4.25 7.32 50.27 4.22 7.32 36 43

C14H19ClN2O3 298.77 76-78 56.94 6.34 10.25 56.28 6.41 9.37 37 44

C14H15ClN2O2 278.74 123-124 60.88 5.58 9.91 60.33 5.42 10.05 38 45

C18H24N2O2 300.40 94-96 71.89 8.08 9.28 71.97 8.05 9.32 39 46

C18H28N2O3 320.44 oil b 40 47

C14H19FN2O3 282.32 72-73 59.32 6.84 9.81 59.56 6.78 9.92 41 48

C18H26N2O2 302.42 79-80 71.25 8.79 9.36 71.49 8.67 9.26 42 49

C14H17F3N2O2 302.30 110.5-112   55.64 5.77 9.26 55.63 5.67 9.26 43 50

C14H15FN2O2 262.29 94-96 64.29 5.47 10.70 64.11 5.76 10.68

Footnotes for Table 3:

Footnote a: IR: 3296, 2980, 2943, 2877, 1638, 1545, 1400, 1377, 1330,1203, 1166, 1127, 1073, 706 cm⁻¹.

Footnote b: IR: 3319, 2963, 2872, 1634, 1549, 1469, 1403, 1327, 1269,1184, 1130, 1083, 818 cm⁻¹.

What is claimed is:
 1. A compound of formula (1)

wherein: R¹ is substituted or unsubstituted aryl; R₂ is hydrogen,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted cyclic alkyl, substituted or unsubstituted cyclic alkenyl,or substituted or unsubstituted aryl; and R³ is hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted cyclic alkyl, orsubstituted or unsubstituted cyclic alkenyl. and pharmaceuticallyacceptable addition compounds thereof.
 2. A compound according to claim1 wherein R¹ is a substituted or unsubstituted aryl group selected fromphenyl and naphthyl.
 3. A compound according to claim 1 wherein R¹ has1, 2 or 3 substituent groups.
 4. A compound according to claim 1,wherein R¹ is substituted with one or more substituent groups selectedfrom halo, trifluoromethyl, tertiary-butyl, CN and phenyl.
 5. A compoundaccording to claim 4 wherein said halo group is fluoro or chloro.
 6. Acompound according to claim 1 wherein R¹ has 1 substituent and is ameta- or para-substituted phenyl group.
 7. A compound according to claim1 wherein R¹ is 3-chlorophenyl, 4-chlorophenyl, 3-fluorophenyl,4-fluorophenyl, 3-(trifluoromethyl)phenyl, 4-(trifluoromethyl)phenyl,3,4-dichlorophenyl or 3,4-difluorophenyl.
 8. A compound according toclaim 1 wherein R¹ is selected from a 2,4-disubstituted phenyl, a2,5-disubstituted phenyl, a 3,4-disubstituted phenyl and a3,5-disubstituted phenyl.
 9. A compound according to claim 1 wherein R¹is substituted by two halo groups, the same or different, or by twotrifluoromethyl groups.
 10. A compound according to claim 9 wherein R¹is dichloro or difluoro-substituted.
 11. A compound according to claim 1wherein R² is H.
 12. A compound according to claim 1 wherein R² is C₁₋₄alkyl.
 13. A compound according to claim 1 wherein R² ismono-substituted phenyl.
 14. A compound according to claim 1 wherein R³is alkyl.
 15. A compound according to claim 1 wherein R³ is C₁₋₄ alkyl.16. A compound according to claim 1 wherein R³ is alkenyl, alkynyl,hydroxyalkyl or alkoxyalkyl.
 17. A compound according to claim 1 whereinR³ is unsubstituted saturated cyclic or acyclic hydrocarbyl.
 18. Acompound according to claim 1 wherein R³ is selected from propyl,2-propenyl, 2-propynyl and 2-hydroxypropyl.
 19. A compound according toclaim 1 wherein R³ is H.
 20. A compound according to claim 1 wherein thecompound is selected from 3-(4-Chlorobenzyloxy)-N-(2-propenyl)azetidine-1-carboxamide,3-(3,4-Dichlorobenzyloxy)-N-(2-propenyl)azetidine-1-carboxamide,3-(3-(Trifluoromethyl)benzyloxy)-N-(2-propenyl)azetidine-1-carboxamide,3-(4-(Trifluoromethyl)benzyloxy)-N-(2-propenyl)azetidine-1-carboxamide,3-(4-Fluorobenzyloxy)-N-(2-propenyl)azetidine-1-carboxamide,3-(Bis(4-chlorophenyl)methoxy)-N-(2-propenyl)azetidine-1-carboxamide,(R)-3-(Bis(4-chlorophenyl)methoxy)-N-(2-hydroxypropyl)azetidine-1-carboxamide,3-(1-(3-Trifluoromethylphenyl)ethyloxy)-azetidine-1-carboxamide and3-(3-(trifluoromethyl)benzyloxy)-azetidine-1-carboxamide.
 21. Apharmaceutical composition comprising a compound according to claim 1 incombination with a pharmaceutically acceptable carrier or excipient. 22.A method of treatment of CNS disorders comprising administering to apatient in need of such treatment an effective dose of a compoundaccording to claim
 1. 23. A method according to claim 22 wherein saidmethod is for the treatment of anxiety, epilepsy, insomnia, alcoholwithdrawal syndrome, chronic and acute pain, neurodegenerative diseases,symptoms relating to withdrawal from substance abuse or spasticity. 24.A method according to claim 22 wherein said method is for the treatmentof anxiety or epilepsy.
 25. A method of muscle relaxation prior tosurgery or surgical manipulation or a method of pre-medication prior tosurgery, comprising administering to a patient in need thereof aneffective dose of a compound according to claim
 1. 26. A methodaccording to claim 23 wherein said insomnia is travel insomnia.
 27. Amethod according to claim 23 wherein said insomnia is insomniaassociated with terminal illness.